Isoform-specific roles of GSK3 in synaptic transmission and plasticity

Resumen

Processes of synaptic plasticity are fundamental mechanisms by which neurons alter the strength of their connections. Such changes are likely to encode aspects of an organism’s interaction with its environment. Indeed, paradigmatic forms of plasticity such as long-term potentiation (LTP) and long-term depression (LTD) are thought to be important molecular events during the formation and refinement of certain types of memory. Both LTP and LTD are also frequently dysregulated in pathologies of the nervous system such as Alzheimer’s disease, which may be responsible for the devastating failure of memory in this condition. Glycogen synthase kinase 3 (GSK3) is a central player in Alzheimer’s disease, and has also been shown to be required for LTD and mediate the balance between different forms of plasticity at the synapse. For these reasons, it has been considered as a therapeutic target. GSK3 exists as two isoforms, GSK3α and GSK3β, of which the importance of the α isoform has been frequently overlooked. A major unknown is which of the two GSK3 isoforms is involved in mediating LTD. Here, we specifically target the GSK3 isoforms with shRNA knockdown and novel isoform-selective drugs to dissect their roles in LTD. Using electrophysiological and live imaging approaches, we find that GSK3α, but not GSK3β, is required for LTD, and is transiently anchored in dendritic spines during LTD induction. Interestingly, we also find that the microtubule-binding protein tau, which plays key roles in Alzheimer’s disease, is required for this spine anchoring of GSK3α, and for GSK3α-induced LTD. Under conditions of synaptic activity, therefore, GSK3α induces LTD through tau. We also examined the role of GSK3 in controlling synaptic transmission under basal conditions. Surprisingly, we found that GSK3 activity is required to maintain synaptic transmission. Postsynaptic GSK3 was involved in this process, and loss of transmission following blockade of GSK3 activity was expressed postsynaptically. Both isoforms of GSK3 needed to be knocked down in the postsynapse for transmission to be depressed, implying that the activity of either isoform is able to maintain synaptic transmission. The results in this PhD thesis highlight GSK3α as a potential therapeutic target for the alleviation of memory deficits during Alzheimer’s disease, and emphasise the importance of isoform-specific targetting of GSK3 more generally, given its vital roles in fundamental synaptic functions